Pyrrolidine-substituted flavones as radio-sensitizers for use in the treatment of cancer

a technology of pyrrolidine and flavone, which is applied in the field of combination for the treatment of cancer, can solve the problems of insufficient oxygen, inability to further enhance the radiation effect, and inability to meet the needs of oxygen,

Active Publication Date: 2014-11-25
PIRAMAL ENTERPRISES LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]In a still further aspect, the present invention relates to the use of a CDK inhibitor selected from the compounds of formula I as a radiosensitizer that enhances the efficacy of radiotherapy for the treatment of cancer.

Problems solved by technology

Most radiosensitizing agents that are useful in the treatment of cancer have been identified from empiric laboratory or clinical observations, without adequate knowledge of the molecular basis of interaction of these agents.
Early experiments indicated that a modest amount of oxygen was required for DNA injury at the moment that radiation was administered; but that once a threshold level of oxygen was present (e.g. as in normal tissues) giving more oxygen would not further enhance the radiation effect.
Despite the importance of the phenomenon of hypoxia, efforts addressing tumor hypoxia have not been successful.

Method used

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  • Pyrrolidine-substituted flavones as radio-sensitizers for use in the treatment of cancer
  • Pyrrolidine-substituted flavones as radio-sensitizers for use in the treatment of cancer
  • Pyrrolidine-substituted flavones as radio-sensitizers for use in the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 1-Methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydro pyridine

[0102]1-methyl-4-piperidone (340 g, 3.0 mol) was added slowly, to a solution of 1,3,5-trimethoxybenzene (500 g, 2.97 mol) in glacial acetic acid (600 mL), maintaining the temperature of the reaction mixture below 40° C. Conc. HCl (450 mL) was added over 20 min. The temperature was raised to 85-90° C. and the reaction mixture was stirred for 3.5 h. It was allowed to cool to 40° C., poured over crushed ice (4 kg) and stirred for 20 min. The precipitate of unreacted 1,3,5-trimethoxybenzene was filtered off. The filtrate was basified, below 10° C., to pH 11-12 using a 50% aqueous NaOH solution. The off white solid obtained was filtered, washed with water and dried to obtain the compound, 1-methyl-4-(2,4,6-trimethoxy-phenyl)-1,2,3,6-tetrahydropyridine.

[0103]Yield: 580 g (74%); mp: 112-114° C.; IR (KBr): 3045, 2900, 2837, 1600, 1585 cm−1; 1H NMR (CDCl3, 300 MHz): δ 6.15 (s, 2H), 5.55 (s, 1H), 3.85 (s, 3H), 3.75 ...

example 2

Preparation of (±)-trans-1-Methyl-4-(2,4,6-trimethoxyphenyl)-piperidin-3-ol

[0104]Boron trifluoride diethyl etherate (300 mL, 2.36 mol) was added slowly with stirring, under an atmosphere of nitrogen, at 0° C., to a solution of compound of example (1) (300 g, 1.14 mol) and NaBH4 (75 g, 1.97 mol) in dry THF (2.25 L). The temperature of the reaction mixture was slowly raised to 55° C. and stirred for 1.5 h. It was cooled to 30° C. Ice cold water (100 mL) was slowly added followed by acidification with conc. HCl (375 mL). The reaction mixture was stirred for 1 h. at 50-55° C. It was cooled to 30° C. and basified using 50% aqueous NaOH solution to pH 11-12. Hydrogen peroxide (30%, 225 mL) was added over 0.5 h. The reaction mixture was stirred at 55-60° C. for 1.5 h. It was cooled to 30° C. and sufficient water was added to dissolve the precipitated salts. The organic layer was separated and the aqueous portion extracted with ethyl acetate (2×1 L). The organic extracts were dried (anhydro...

example 3

Preparation of (±)-trans-Acetic acid-1-methyl-3-(2,4,6-tri ethoxyphenyl)-pyrrolidin-2-yl methyl ester

[0107]Methanesulfonyl chloride (30.27 mL, 44.8 g, 0.4 mol) was added drop wise to a cooled and stirred solution of compound of example (2) (100 g, 0.35 mol) and triethylamine (71.88 g, 0.7 mol) in dry THF (1.0 L). The reaction mixture was further stirred for 45 min. at 0° C. The precipitate of triethylamine HCl was filtered and washed with dry THF (2×100 mL). The filtrate was added dropwise to a refluxing suspension of sodium acetate (115 g, 1.40 mol) in 2-propanol (1.0 L). The reaction mixture was refluxed for a further 15 min., diluted with EtOAc (1.0 L) and salts were filtered. The mixture of salts was washed with EtOAc (2×100 mL). The combined filtrate was concentrated to give a gum. Water (50 mL) was added to the gum with stirring to obtain a solid which was filtered and dried to yield the compound, (±)-trans-acetic acid 1-methyl-3-(2,4,6-trimethoxy-phenyl)-pyrrolidin-2-yl methy...

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Abstract

The present invention relates to a combination for the treatment of cancer wherein the combination exhibits a synergistic effect. The combination comprises radiation and at least one cyclin dependent kinase (CDK) inhibitor selected from the compounds of formula I or a pharmaceutically acceptable salt or a solvate thereof. The present invention also relates to a method for the treatment of cancer, which method comprises administering to a patient in need of such a treatment, a therapeutically effective amount of the combination. The present invention also relates to the use of a CDK inhibitor selected from the compounds of formula I as a radiosensitizer that enhances the efficacy of radiotherapy for the treatment of cancer, particularly head and neck cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a 371 of International Application PCT / IB2010 / 051921 filed 3 May 2010, which claims the benefit of Indian Application No. 1174 / MUM / 2009 filed 5 May 2009 and U.S. Provisional Application No. 61 / 224,524 filed 10 Jul. 2009.FIELD OF THE INVENTION[0002]The present invention relates to a combination for the treatment of cancer wherein the combination exhibits a synergistic effect. The combination comprises radiation and at least one cyclin dependent kinase (CDK) inhibitor selected from the compounds of formula I (as described herein) or a pharmaceutically acceptable salt or a solvate thereof. The present invention also relates to a method for the treatment of cancer, particularly head and neck cancer, which method comprises administering to a patient in need of such a treatment, a therapeutically effective amount of the combination. The present invention also relates to the use of a CDK inhibitor selected from the compounds ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D311/32A61K31/4025A61K31/00A61P35/00
CPCA61K2300/00A61K31/00A61K31/4025A61P1/04A61P1/16A61P1/18A61P11/00A61P15/00A61P25/00A61P35/00A61P35/02A61P43/00
Inventor RATHOS, MAGGIE JOYCEJOSHI, KALPANA SANJAYHEBBAR, NIKHIL KRISHNAMURTHYSHARMA, SOMESH
Owner PIRAMAL ENTERPRISES LTD
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